How is severe combined immunodeficiency (SCID) diagnosed?

Updated: May 27, 2020
  • Author: Francisco J Hernandez-Ilizaliturri, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

The diagnosis of SCID should be suspected in children with any of the following conditions:

  • Unexplained lymphopenia
  • Failure to thrive
  • Chronic diarrhea
  • Recurrent severe episodes of infection with respiratory syncytial virus (RSV), herpes simplex virus (HSV), varicella-zoster virus (VZV), measles, influenza, or parainfluenza
  • A family history of SCID

Patients with suspected SCID require complete evaluation of specific humoral and cellular immunity, which includes measurement of immunoglobulin levels, antibody titers, lymphocyte subsets, and assessment of T-cell function. This can be done via evaluating the responses to mitogens in vitro.

The probable diagnosis of SCID is based on the following:

  • A T-cell count less than 20% of lymphocytes, an absolute lymphocyte count of less than 3,000 cells/mm3, and a response to mitogens of less than 10% of the control or maternal T cells in the circulation

  • At this point, establish a molecular diagnosis and also consider the sex, family history, and phenotype of the patient.

  • Quantitative measurement of the serum immunoglobulins and IgG subclasses is necessary to confirm the diagnosis of B-cell deficiency. If, despite normal results, humoral immunodeficiency is suggested, the antibody response to specific antigens (polysaccharide or protein antigens) should be evaluated further. In patients with SCID presenting with recurrent infections in the first months of life, immunoglobulin levels are not helpful in the diagnosis, owing to the presence and persistence of maternal antibodies.

Levels of serum immunoglobulin are determined by serum protein electrophoresis.

Quantitative methods are used for the precise measurement of each immunoglobulin isotype. Enzyme-linked immunosorbent assays (ELISAs) are used for IgE quantitation.

Compare values to age-standardized reference ranges for each laboratory. The following are examples of values that are used for the adult population:

  • IgG1 – 500-1200 mg/dL
  • IgG2 – 200-600 mg/dL
  • IgG3 – 50-100 mg/dL
  • IgG4 – 20-100 mg/dL
  • IgM – 50-150 mg/dL
  • IgA1 – 50-200 mg/dL
  • IgA2 – 0-20 mg/dL
  • IgD – 0-40 mg/dL
  • IgE – 0-0.2 mg/dL
  • In most disorders involving IgG, the level is less than 200-250 mg/dL. Levels of the other immunoglobulins vary depending on the underlying disease.

  • Immunoglobulin subclass deficiency is defined as a decrease of an IgG subclass greater than 2 standard deviations (SDs) below the normal mean for age.

Antibody response after immunization may be absent.

  • Check the antitetanus/diphtheria antibodies (IgG1), antipneumococcal polysaccharide antibodies (IgG2), and antirespiratory virus antibodies (IgG3) if the titers for the total immunoglobulins are within the reference ranges and the patient is unable to produce antibodies to specific antigens.

  • Antibody response is evaluated by measuring antitetanus and antipneumococcal titers 3-4 weeks after vaccination; a rise of 4-fold for antitetanus and 2-fold for antipneumococcal titers is considered normal.

The absence of isohemagglutinins is a significant finding that is suggestive of an immunoglobulin production problem. Evaluate IgM antibodies to A and B blood group antigens (isohemagglutinins) if the other test findings are within reference ranges and the patient is unable to mount a response to specific antigens.

Peripheral blood lymphocyte levels should be measured.

  • The lymphocyte count is higher in infancy and childhood than in adulthood. An absolute lymphocyte count of less than 280 per microliter (ie, 2 SDs below the mean) is abnormal.

  • The association of a low lymphocyte count with recurrent infections is very suggestive of immunodeficiency.

Lymphocyte phenotyping using flow cytometry analysis is the next step. The absolute number of B-cells, T-cells, and natural killer (NK) cells is more useful than percentages.

Measuring T-lymphocyte numbers and function may be necessary. Lymphocyte activation (CD45 RA/RO isoformic antigens) and T-cell receptor phenotype (TCR ab/gd lineage) determination may provide additional information regarding the type of immunodeficiency. For example, Omenn syndrome is characterized by a high number of T cells carrying TCRgd or CD45+. Determination of the helper (CD4) to suppressor (CD8) T-cell ratio is sometimes useful.

Cutaneous delayed-type hypersensitivity testing is used to evaluate the anamnestic response of cellular immunity to previously encountered antigens.

  • The test results are not reliable in children younger than age 1 year, and the response is frequently suppressed following viral and bacterial infections and after glucocorticoid therapy.

  • The results are determined by measuring the induration 48-72 hours following an intradermal injection of 0.1 mL of tetanus toxoid (at 1:100 dilution, 0.2 Loeffler U/0.1 mL), mumps skin test antigen, candidal antigen (at 1:100 dilution; if no reaction is present, use 1:10 dilution), tuberculin (0.1 mL containing 2-10 IU of purified protein derivative [PPD]), and trichophytin (1:30 dilution).

  • The test result is considered positive if the induration is greater than 5 mm (or > 2 mm in children).

  • This test can be complemented by in vitro study of lymphocyte proliferation to different mitogens.


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